Splanchnic Glucose Output Research Articles

The influence of a long-acting somatostatin analogue on splanchnic haemodynamics and metabolism in healthy subjects and patients with liver cirrhosis.

The influence of a long-acting somatostatin octapeptide analogue (SMS 201-995) on splanchnic circulation and metabolism has been studied in healthy subjects and in patients with liver cirrhosis. In healthy subjects doses of 5, 10, 50, or 100 micrograms SMS and in the cirrhotic patients 25 micrograms SMS were infused intravenously during 1 h. Measurements were obtained before, during, and for 1 h after SMS infusion. SMS infusion in healthy subjects resulted in a 25-35% reduction in hepatic blood flow. This effect was largely independent of the dose used. Splanchnic oxygen uptake was unchanged before and during SMS infusion. Insulin and glucagon levels fell markedly in response to SMS administration, and the blood concentration and splanchnic output of glucose decreased transiently. Patients with liver cirrhosis responded to SMS infusion similarly to the healthy subjects. Hepatic blood flow decreased by 25-35% and remained suppressed for at least 1 h after infusion. Wedge hepatic venous pressure was 18 +/- 2 mm Hg in the basal state and decreased progressively during and after SMS infusion (60 min after infusion, 15 +/- 2 mm Hg; P less than 0.01). The marked hyperinsulinaemia and hyperglucagonaemia seen in the basal state decreased significantly during SMS administration. As in the case of the controls, blood concentration and splanchnic output of glucose fell transiently during and after SMS infusion. It is concluded that SMS exerts a marked and prolonged suppressive effect on hepatic blood flow in both healthy subjects and patients with liver cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Triiodothyronine increases splanchnic release and peripheral uptake of glucose in healthy humans

To examine the effect of experimental hyperthyroidism induced by triiodothyronine (T3) administration on glucose utilization and glucose-stimulated insulin secretion, euglycemic insulin clamp studies (A), hyperglycemic clamp studies (B), and estimation of splanchnic glucose metabolism after an oral glucose load by means of the hepatic venous catheter technique (C) were performed in healthy volunteers whose serum T3 concentration had been increased from 1.1 +/- 0.02 (SE) to 3.5 +/- 0.2 ng/ml. At plasma insulin concentrations of 77 +/- 6 microU/ml and maintenance of euglycemia, insulin-mediated glucose metabolism (6.8 +/- 0.4 mg X kg-1 X min-1) was not significantly altered following T3 exposure (7.2 +/- 0.7) in study A. When plasma glucose was raised and maintained at 7 mmol/l above basal, glucose uptake (10.6 +/- 0.7 mg X kg-1 X min-1) was increased to 14.6 +/- 2.0 mg X kg-1 X min-1 (P less than 0.02) following T3 administration in study B. In study C, basal splanchnic glucose output (104 +/- 10 mg/min) was markedly augmented when preceded by T3 exposure (167 +/- 17 mg/min; P less than 0.005). After a 75-g glucose load, splanchnic glucose output was enhanced by T3 by 30% (43.4 +/- 2.2 vs. 56.9 +/- 6.6 g/150 min; P less than 0.05), whereas arterial plasma concentrations of glucose, insulin, and C-peptide were not significantly different. It is concluded that in healthy humans, exposure to elevated plasma concentrations of T3 increases the amount of glucose to be released from the splanchnic bed. Glucose tolerance, however, remains unaltered, because peripheral glucose uptake is increased at the same time.

The effect of growth hormone on splanchnic glucose and substrate metabolism following oral glucose loading in healthy man.

Elevated plasma concentrations of growth hormone impair glucose tolerance and insulin sensitivity of peripheral tissues. To study the effect of short-term exposure to growth hormone concentrations elevated into the upper physiologic range (7-10 ng/ml) on splanchnic carbohydrate metabolism, both splanchnic glucose output (SGO) and substrate exchange after ingestion of a 75-g glucose load were determined by means of the liver vein catheter technique in six healthy volunteers after growth hormone administration. Growth hormone was infused at a rate of 2 micrograms/kg X h starting 120 min before and continuing for 150 min following the glucose load. Control studies without growth hormone administration were performed in seven subjects. SGO was 104 +/- 10 (SEM) mg/min in the postabsorptive state and increased to 43.4 +/- 2.2 g during the 150-min period following glucose ingestion. Growth hormone infusion did not alter basal SGO (130 +/- 14 mg/min), nor the splanchnic exchange of lactate, pyruvate, and free fatty acids, whereas basal production of beta-OH-butyrate was increased twofold; following glucose ingestion a higher proportion of the given glucose load escaped the splanchnic bed after growth hormone exposure (66.9 +/- 6.8 g/150 min; P less than 0.005). The insulin production rate (basal 14 +/- 2 mU/min; following oral glucose 7.0 +/- 0.8 U/150 min) as calculated from C-peptide release from the splanchnic area was unaltered by growth hormone exposure in the basal state (14 +/- 3 mU/min), but augmented after glucose ingestion (14.8 +/- 1.5 U/150 min).(ABSTRACT TRUNCATED AT 250 WORDS)

The 75-g oral glucose tolerance test: effect on splanchnic metabolism of substrates and pancreatic hormone release in healthy man.

To determine the effect of the 75 g oral glucose tolerance test on carbohydrate and lipid metabolism, the splanchnic exchange of glucose, lactate, pyruvate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate as well as the release of insulin, C-peptide, glucagon and pancreatic polypeptide were evaluated in eight healthy male volunteers in the basal state and for 150 min following glucose ingestion. Oral glucose loading was followed by a rapid rise in splanchnic output of glucose (mean +/- SEM; 154 +/- 12 mmol/150 min), pyruvate (1.2 +/- 1.2 mmol/150 min) and lactate (8.6 +/- 2.0 mmol/150 min), whereas there were reductions in the splanchnic uptake of non-esterified fatty acids (-10.7 +/- 4.4 mmol/150 min) and the splanchnic output of beta-hydroxybutyrate (-4.8 +/- 3.3 mmol/150 min) and acetoacetate (-3.0 +/- 1.2 mmol/150 min). In parallel, splanchnic output of insulin (12.3 +/- 2.7 nmol/150 min), C-peptide (36.1 +/- 5.0 nmol/150 min) and transiently of pancreatic polypeptide rose, whereas that of glucagon fell (-0.58 +/- 0.21 nmol/150 min). Even at 150 min after glucose ingestion, splanchnic output and arterial concentrations of glucose, lactate, insulin and C-peptide were still above their respective basal values while those of non-esterified fatty acids and glucagon were reduced. Taking into account the partial suppression of endogenous glucose production by ingested glucose it is concluded that, in normal postabsortive man, only 49-63% of a 75 g oral glucose load is retained by the splanchnic bed during the first 150 min, the rest being available for non-hepatic tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Splanchnic exchange of glucose, amino acids and free fatty acids in patients with chronic inflammatory bowel disease.

In order to study arterial concentrations and splanchnic exchange of substrates and hormones in patients with chronic inflammatory bowel disease three patients with Crohn's disease and four with ulcerative colitis were studied using the hepatic venous catheter technique. Systemic turnover and regional exchange of free fatty acid were evaluated using intravenous infusion of 14C-labelled oleic acid. All measurements were made in the postabsorptive, overnight fasted state. Arterial glucose concentrations were 10% lower in the patients but net splanchnic glucose output was similar in patients and controls. Glucose precursor uptake (lactate, pyruvate, and glycerol), however, was increased two to five fold in the patients. Arterial amino acid concentrations were generally reduced but net splanchnic amino acid uptake was the same in patients and controls. Arterial concentrations of free fatty acid and oleic acid as well as systemic and fractional turnover were similar in patients and controls. The patients' splanchnic uptake of oleic acid was increased more than three fold in comparison with controls. Splanchnic release of oleic acid was also augmented in the patients. Both arterial concentrations and splanchnic production of ketone bodies were raised in the patients. The proportion of splanchnic free fatty acid uptake which could be accounted for by ketone body production was significantly greater in the patients (37 +/- 4%) than the controls (20 +/- 5%, p less than 0.025). Estimated hepatic blood flow was 55% greater (p less than 0.01) in the patients as compared with the controls (1930 +/- 150 vs 1240 +/- 70 ml/min), while splanchnic oxygen uptake was similar in the two groups. From these findings it is concluded that patients with chronic inflammatory bowel disease show (1) markedly increased hepatic blood flow, reflecting an inflammatory hyperaemia in the splanchnic region, (2) a normal net splanchnic glucose output, (3) accelerated hepatic gluconeogenesis as well as ketogenesis, probably as a consequence of the altered hormonal milieau, and (4) low concentrations of most amino acids possibly because of protein malabsorption. These findings underscore the importance of adequate protein and carbohydrate administration to this patient group.

Splanchnic glucose metabolism during leg exercise in 60-hour-fasted human subjects.

An increased mobilization of the hepatic glycogen is necessary for the maintenance of glucose homeostasis during exercise. To examine the effect of exercise on glucose metabolism when the hepatic glycogen stores are depleted, five prolonged-fasted (60-h, PF) subjects were investigated. Arterial concentrations and splanchnic exchange of glucose and gluconeogenic precursors were studied at rest and during exercise (40 min, 60% of VO2max) using the hepatic venous catheter technique. Five overnight-fasted subjects (OF) served as controls. In the resting state, arterial glucose concentration (3.0 +/- 0.2 mmol/liter) and splanchnic glucose output (SGO) (0.3 +/- 0.1 mmol/min) were 30 and 55% lower, respectively, in the PF than in the OF subjects. During exercise SGO rose in both groups, but the increase was smaller in the PF subjects so that at the end of work SGO (0.9 +/- 0.2 mmol/min) was only one-third of that in the OF group (2.5 +/- 0.4 mmol/min). During exercise in the PF state the arterial lactate concentration (5.0 +/- 1.1 mol/liter) and the splanchnic lactate uptake (1.1 +/- 0.3 mmol/min) were threefold and twofold higher, respectively, than in the OF state. In the PF state, the splanchnic uptake of gluconeogenic precursors could account for more than 80% of the splanchnic glucose production both at rest and during exercise. Despite the lower SGO in the PF state, blood glucose concentrations rose during exercise, indicating a diminished peripheral glucose uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans.

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production.

Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man.

We investigated the effects of hyperinsulinemia and hyperglycemia on peripheral glucose uptake, hepatic glucose production, and splanchnic glucose uptake in man. Euglycemic and hyperglycemic clamp studies were carried out in 37 healthy subjects in combination with hepatic vein catheterization and [3H-3]glgcose infusion. In the basal state, hepatic glucose production ([3H-3]glucose) exceeded net splanchnic glucose output (catheter) in every subject (2.3 ± 0.04 versus 1.7 ± 0.07 mg/min · kg, P < 0.001), indicating uptake of glucose by the splanchnic region at a rate of 0.6 ± 0.05 mg/ min · kg. In agreement with this estimate, [3H-3]glucose concentration was consistently lower in hepatic venous than in arterial blood, by 3.0 ± 0.2% (P < 0.001). When plasma insulin levels were raised to 37 ± 2, 53 ± 2, 101 ± 2, 428 ± 37, and 1189 ± 14 μU/ml, with maintenance of euglycemia, total glucose uptake rose to 2.9 ± 0.4, 3.9 ± 1.0, 5.1 ± 0.4, 9.9 ±1.1, and 11.8 ± 1.3 mg/min · kg, respectively. The whole body glucose clearance rose significantly above baseline at each hyperinsulinemic plateau (P < 0.05 or less). Hepatic glucose production fell by 68% (P < 0.01) at the lowest hyperinsulinemic level, by 87% at insulin levels of 53 ± 2 μU/ml, and by over 95% with each higher insulin dose. Splanchnic glucose uptake was not significantly increased over basal values at any insulin concentration. When plasma glucose levels were raised to 137 ± 3 and 224 ± 2 mg/dl peripheral plasma insulin levels rose to 20 ± 4 and 55 ± 5 μU/ml, respectively. Total glucose uptake was enhanced (2.5 ± 0.4 and 5.3 ± 1.0 mg/min · kg, P < 0.05 and P < 0.01, respectively). Suppression of hepatic glucose production was <90% at the lower hyperglycemic level, and virtually complete at the higher one. Splanchnic glucose uptake was not changed by mild hyperglycemia (0.5 ± 0.05 mg/min · kg), but rose significantly (1.3 ± 0.3 mg/ min · kg, P < 0.01) with further hyperglycemia. The latter effect resulted primarily from increased glucose delivery to the splanchnic area, since the splanchnic glucose extraction ratio (4.0 ± 0.3%) was not different from baseline (3.0 ± 0.3%). When hyperglycemia (224 ± 1 mg/dl) was combined with a somatostatin infusion, thereby reducing plasma insulin from 15 ± 3 to 10 ± 1 μU/ml (P < 0.01), both total glucose uptake (2.8 ± 0.03 mg/min · kg) and clearance (1.3 ± 0.01 mg/min · kg) were significantly (P < 0.01) lower than in the hyperglycemic studies in which insulin secretion was not blocked. Hepatic glucose production, however, was effectively suppressed (by 74%, P < 0.001), whereas splanchnic glucose uptake was only slightly increased above baseline. Replacement of insulin (via an exogenous infusion at a rate of 0.3 mU/min · kg) restored total glucose uptake, splanchnic glucose uptake, and suppression of hepatic glucose production to the levels seen with hyperglycemia without somatostatin. When hyperglycemia (216 ± 2 mg/dl) was combined with somatostatin and glucagon replacement (no insulin), hepatic glucose production was still suppressed by 47 ± 1% to 1.18 ± 0.01 mg/kg · min (P < 0.001 versus hyperglycemia + SRIF without glucagon replacement). The results indicate that both hyperglycemia and hypoglucagonemia contribute to the decline in hepatic glucose production following somatostatin infusion. In conclusion, hyperinsulinemia alone stimulates glucose uptake by peripheral but not splanchnic tissues. The dose-response characteristics of stimulation of peripheral glucose uptake and inhibition of hepatic glucose production by insulin are very different, the half-maxima being ∼120 and ∼50 μU/ml, respectively. Hyperglycemia enhances glucose uptake by both peripheral and splanchnic tissues, but this action requires an intact endogenous insulin response. In contrast, hyperglycemia can suppress endogenous glucose production even in the presence of low insulin levels.

Insulin production rate, hepatic insulin retention and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetes mellitus.

To differentiate peripheral and hepatic insulin resistance in hyperinsulinaemic overweight Type 2 (non-insulin-dependent) diabetic patients (n = 17; 143 +/- 4% ideal body weight; mean +/- SEM) arterial concentrations and splanchnic exchange of glucose, pyruvate, lactate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate, as well as the insulin production rate, were determined before and during oral glucose loads of 25 g or 100 g. Insulin production rate, hepatic insulin retention and splanchnic exchange of glucose and metabolites were estimated by means of the hepatic venous catheter technique. In the basal state insulin production rate was greater in overweight Type 2 diabetic patients (2.57 +/- 0.28 pmol.kg-1. min-1) than in healthy control subjects (1.68 +/- 0.17 pmol.kg-1.min-1; p less than 0.01). After ingestion of 25 g glucose, the cumulative insulin production rate exceeded normal values (p less than 0.05), but was below normal with 100 g glucose (p less than 0.01). Relative insulin trapping by the splanchnic bed in the diabetic patients was 54 +/- 3%, not different from normal. Following a 100 g glucose load, splanchnic insulin retention fell by 20% in the patients, and less consistently so in healthy controls. Splanchnic glucose output was normal in the diabetic patients both in the basal state and after glucose ingestion although the induced arterial blood glucose levels were greater in the diabetic patients than in control subjects (p less than 0.005). Splanchnic output of pyruvate (p less than 0.025), lactate (p less than 0.01), and beta-hydroxybutyrate (p less than 0.005) were greater in the basal state in the diabetic patients than in healthy subjects. However, no difference in splanchnic exchange was seen between the two groups in their metabolites' respective response to glucose ingestion. These data suggest that obese hyperinsulinaemic Type 2 diabetic patients may represent a subgroup of diabetic patients with predominantly peripheral, but compensated hepatic, insulin resistance being associated with an increased basal insulin production rate which only exhausts after ingestion of a large glucose load.

Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man.

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg(-1) min(-1)) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg(-1) min(-1); (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg(-1) min(-1)); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg(-1) min(-1)). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls ( approximately 170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 muU/ml at 90 min. NSGB switched from a net output of 1.71+/-0.13 to a net uptake of 1.5-1.6 mg kg(-1) min(-1) due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78+/-0.13 to 1.6-1.8 mg kg(-1) min(-1); P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 muU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 muU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 muU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg(-1) min(-1)). Peripheral glucose uptake rose to the same extent as in controls. IT IS CONCLUDED THAT: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

Role of the kidney in the metabolism of fructose in 60-hour fasted humans.

Arterial (A) and renal venous (RV) concentrations and net splanchnic exchange of glucose, fructose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during a 135-min intravenous infusion of fructose at 2 mmol/min in healthy subjects after a 60-h fast. After 45 min of the fructose infusion, somatostatin (9 microgram/min) was infused for 60 min to induce hypoglucagonemia. Fructose infusion resulted in a net uptake of this hexose by the kidney as well as the splanchnic bed. Estimated renal uptake of fructose could account for the disposal of 20% of the administered fructose load while splanchnic uptake accounted for 38%. The fructose infusion resulted in a rise in blood glucose of 0.9 mmol/L, a 35% increase in net glucose output from the splanchnic bed, and a consistent net output of glucose from the kidney (A-RV = -0.17 +/- 0.05 mmol/L as compared with 0 +/- 0.03 in the basal state, P less than 0.02). Net glucose release from the kidney could account for 55% of the net renal uptake of fructose. The fructose infusion also resulted in a marked change in renal lactate balance from a net uptake in the basal state (A - RV = 0.05 +/- 0.01 mmol/L) to a net output during fructose administration (A - RV = -0.10 +/- 0.04). Administration of somatostatin resulted in a fall in arterial glucagon levels and a 35% decrease in splanchnic glucose output but failed to alter the arterial-renal venous difference for glucose observed during the fructose infusion. We conclude that in 60-h fasted man: (a) intravenous infusion of fructose results in a net uptake of this hexose by the kidney as well as the liver, (b) this uptake is accompanied by stimulation of renal as well as hepatic glucose production and renal production of lactate, and (c) hypoglucagonemia inhibits splanchnic but not renal glucose output during fructose infusion. These data indicate that the kidney is an important site of fructose disposal and that glucose and lactate are end products of renal fructose metabolism.

Mechanisms of Epinephrine-induced Glucose Intolerance in Normal Humans

To evaluate the role of the splanchnic bed in epinephrine-induced glucose intolerance, we selectively assessed the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose production, and peripheral glucose uptake by combining infusion of [3-(3)H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg(-1) per min(-1)) or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg(-1) per min(-1)); and (b) in amounts identical to the control study. During infusion of glucose alone, blood glucose rose twofold, insulin levels and net posthepatic insulin release increased three- to fourfold, and net splanchnic glucose output switched from a net output (1.65+/-0.12 mg/kg(-1) per min(-1)) to a net uptake (1.56+/-0.18). This was due to a 90-95% fall (P < 0.001) in hepatic glucose production and a 100% rise (P < 0.001) in splanchnic glucose uptake (from 0.86+/-0.14 to 1.71+/-0.12 mg/kg(-1) per min(-1)), which in the basal state amounted to 30-35% of total glucose uptake. Peripheral glucose uptake rose by 170-185% (P < 0.001). When epinephrine was combined with the lower glucose dose, blood glucose, insulin release, and hepatic blood flow were no different from values observed with glucose alone. However, hepatic glucose production fell only 40-45% (P < 0.05 vs. glucose alone) and, most importantly, the rise in splanchnic glucose uptake was totally blocked. As a result, splanchnic glucose clearance fell by 50% (P < 0.05), and net splanchnic glucose uptake did not occur. The rise in peripheral glucose uptake was also reduced by 50-60% (P < 0.001). When epinephrine was added to the same dose of glucose used in the control study, blood glucose rose twofold higher (P < 0.001). The initial rise in splanchnic glucose uptake was totally prevented; however, beyond 30 min, splanchnic glucose uptake increased, reaching levels seen in the control study when severe hyperglycemia occurred. Splanchnic glucose clearance, nevertheless, remained suppressed throughout the entire study (40%-50%, P < 0.01). It is concluded that (a) the splanchnic bed accounts for one-third of total body glucose uptake in the basal state in normal humans; (b) epinephrine markedly inhibits the rise in splanchnic glucose uptake induced by infusion of glucose; and (c) this effect does not require a fall in insulin and is modulated by the level of hyperglycemia. Our data indicate that the splanchnic bed is an important site of glucose uptake in post-absorptive humans and that epinephrine impairs glucose tolerance by suppressing glucose uptake by both splanchnic and peripheral tissues, as well as by its well known stimulatory effect on endogenous glucose production.

Glucose oxidation in relation to the size of the oral glucose loading dose

Using “naturally labeled 13C-glucose” the conversion to expired air CO 2 of 100, 66 and 33 g oral glucose loads was evaluated, during 7 hr, in 6 male healthy volunteers. The total amounts of exogenous glucose converted to expired air CO 2 were proportional to the loading doses and averaged, in g/7 hr, 14.6 ± 2.1 for 33 g, 20.8 ± 2.1 for 66 g and 31.2 ± 1.6 for 100 g. In contrast total glucose oxidation, evaluated by indirect calorimetry, was similar in the three groups and was not correlated with the dose of glucose given. The plasma insulin response was significantly correlated with the load of glucose ( r = 0.86; p < 0.001) whereas such correlation was not observed with the blood glucose response. Comparison with data available in the literature on the influence of the size of the oral glucose load on endogenous glucose production and on splanchnic glucose output suggests that the greater oxidation of exogenous glucose seen when the oral load of glucose is increased essentially results from a greater enrichment of the systemic glucose pool with exogenous glucose.

Effect of buformin on splanchnic carbohydrate and substrate metabolism in healthy man

The effect of buformin (100 mg b.i.d. for 5 days) on carbohydrate metabolism, both splanchnic glucose output (SGO) and net substrate exchange were studied in 6 healthy male volunteers in the basal state and following glucose ingestion (100 g). Control studies without buformin were also performed in 5 men. Splanchnic glucose and substrate exchange was determined by means of the hepatic venous catheter technique. SGO was 154 ± 18 (SEM) mg/min in the postabsorptive state and increased 33.3 ± 2.8 g above the basal level during the 150 min period following glucose ingestion. Buformin administration did not alter basal SGO (157 ± 26 mg/min), nor the splanchnic exchange of pyruvate, alanine, glycerol, OH-butyrate and acetoacetate. Splanchnic lactate balance was altered by buformin and net lactate output occurred. Following glucose ingestion the rise in splanchnic lactate output was increased, whereas no change in SGO ( 32.9 ± 3.5 g 150 min ) and splanchnic exchange of the other substrates was observed. The increase in arterial blood glucose concentration following oral glucose loading was reduced by buformin pretreatment ( p < 0.0005). The insulin production rate (basal, 16 ± 2 mU/min; following oral glucose, 13 ± 2 U 150 min ) as calculated from C-peptide release from the splanchnic area was unchanged by buformin. Except for a marked rise in splanchnic lactate production, buformin did not alter splanchnic carbohydrate metabolism after orally ingested glucose in healthy man. The diminished increase in arterial blood glucose concentration associated with unaltered insulin production suggests that buformin facilitates glucose utilization by peripheral tissues.

Influence of hyperthyroidism on splanchnic exchange of glucose and gluconeogenic precursors.

Arterial concentrations and splanchnic exchange of glucose, amino acids, lactate, pyruvate, and glycerol were determined in 14 hyperthyroid patients and 12 healthy controls. Seven of the patients were restudied after 5-12 mo of medical management at which time there was chemical and clinical evidence of a euthyroid state. The arterial level of glucose was slightly higher (+10%) in the patient group and the glycerol concentration was three times greater among the patients. The plasma levels of the glycogenic amino acids, alanine, glycine, and serine were decreased by 20-30%, while the concentrations of leucine, isoleucine, and tyrosine were increased by 20-80%. The levels of lactate and pyruvate were similar in patients and controls as were insulin and glucagon concentrations. Splanchnic glucose output in the patient group was 35% lower than in controls. However, total splanchnic uptake of glucogenic precursors was 100% higher than in controls and showed a direct linear correlation with serum triiodothyronine. Total precursor uptake could account for 75% of splanchnic glucose output in the patients, compared to 26% in controls. The increase in uptake of lactate, alanine, and other amino acids was due to a 35-80% rise in splanchnic fractional extraction plus a 20% rise in estimated hepatic blood flow. When the patients were restudied after medical treatment splanchnic exchange of glucose and glucose precursors had reverted to normal values. The present findings demonstrate that in hyperthyroidism (a) total splanchnic glucose output is reduced in relation to controls, (b) splanchnic uptake of gluconeogenic precursors is accelerated, largely due to a rise in fractional extraction of precursor substrates and to a smaller extent, as a result of an increase in hepatic blood flow, and (c) these changes revert to normal when a euthyroid state has been achieved.

Influence of hypoglucagonemia on splanchnic glucose output during leg exercise in man

Summary. The present study was undertaken to examine the role of glucagon in the regulation of hepatic glucose production during exercise. Using the hepatic vein catheter technique, the influence of somatostatin‐induced hypoglucagonemia on splanchnic exchange of glucose and glucose precursors during exercise was studied in normal postabsorptive man. In the experiments hypoglucagonemia was induced 10 min before and during 40 min of supine bicycle exercise (series 1), or 1–2 h before, and during, 40 min of upright bicycle exercise (series 2). The relative work intensities were 50% (series 1) and 55% (series 2) of maximal oxygen uptake. Control studies without somatostatin were conducted in both series.In both series, insulin and glucagon levels were suppressed by 40–50% throughout the period of somatostatin infusion. In series 1, somatostatin infusion at rest resulted in a 50 % fall in splanchnic glucose output. Onset of exercise during suppressed glucose production was followed by a rise in splanchnic glucose output similar to that seen in control subjects, but the absolute rate of glucose production was 5–25 % lower than in controls. In contrast to the euglycemia observed in the control experiment, exercise during somatostatin administration was accompanied by a 1–2 mmol/1 fall in blood glucose concentration due to the lower rate of glucose production.In series 2, a variable glucose infusion was added to the somatostatin administration before exercise to maintain euglycemia. After 1–2 h of somatostatin administration, glucose infusion was no longer required to prevent hypoglycemia, and splanchnic glucose output had returned to the basal level. At this time exercise was started. Both the rise in splanchnic glucose production and the absolute rate of splanchnic glucose output during exercise were similar to those observed without somatostatin. However, exercise during prolonged somatostatin infusion was accompanied by a gradual 50% rise in arterial glucose concentration, whereas no change in blood glucose during exercise was seen in controls.

The contrasting responses of splanchnic and renal glucose output to gluconeogenic substrates and to hypoglucagonemia in 60-h-fasted humans.

SUMMARY Arterial concentrations and splanchnic as well as renal exchange of glucose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during intravenous infusion of alanine or glycerol in healthy subjects who had fasted for 60 h. After 45 min of infusion of alanine or glycerol, somatostatin administration (SRIF, 9 μg/min) was added to induce hypoglucagonemia. Alanine infusion, at a rate of 1 mmol/min, was accompanied by an 80% rise in splanchnic glucose output (SGO) and a small (16%) rise in arterial glucose. Splanchnic alanine uptake, which rose fivefold to sixfold above basal, could account for the entire rise in SGO. Intravenous administration of glycerol (1 mmol/min) resulted in an elevation of blood glucose (+ 9%) but no significant change in SGO, even though glycerol uptake by the splanchnic tissues rose eightfold above basal levels. Measurements of renal exchange of glucose indicated a small but statistically significant release of glucose from the kidney (0.04 ± 0.01 mmol/min) in the basal state, which accounted for 10% of total (renal plus splanchnic) glucose production. Administration of glycerol at a rate of 2 mmol/min resulted in a rise in renal glucose output to 0.16 ± 0.03 mmol/min, which could be accounted for in its entirety by renal glycerol uptake. In contrast, infusion of alanine (2 mmol/min), did not alter the renal glucose exchange. Infusion of SRIF was accompanied by a significant fall in the arterial glucagon level in all studies. Concomitante, large decreases in arterial glucose and SGO were observed during both alanine and glycerol administration. However, splanchnic uptake of gluconeogenic precursors was not influenced by SRIF administration. The elevated renal glucose output seen during glycerol administration was not altered by SRIF infusion. It is concluded that, in 60-h-fasted man, (a) renal glucose output contributes significantly to total glucose production, (b) administration of glycerol stimulates renal glucose production, (c) alanine infusion increases splanchnic but may not affect renal glucose output, and (d) hypoglucagonemia inhibits splanchnic but not renal glucose output. These data indicate that hepatic and renal gluconeogeneses respond differently with respect to stimulation by specific substrates and to their dependence on basal glucagon levels.

Oral glucose tolerance test: Effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

To evaluate the role of splanchnic metabolism in the disposal of orally ingested glucose and thereby to define the optimal glucose load for glucose tolerance testing, splanchnic glucose output (SGO), as determined by the hepatic-venous catheter technique, was estimated in 16 healthy male volunteers in the basal state and after different glucose loads. Following glucose ingestion of 12.5, 25, 50, 75, and 100 g glucose, mean SGO over 2 hours was 9, 10, 12.3, 20, and 24.7 g above basal hepatic glucose production or 72, 40, 25, 26, and 25 percent of the respective glucose load. Increasing glucose doses represented a greater and more prolonged insulinogenic stimulus as determined by insulin concentrations in hepatic venous plasma. Splanchnic lactate uptake decreased and finally reverted to a net output in most of the subjects studied, whereas pyruvate production increased with rising glucose loads. It is concluded that (1) maximal stimulation of insulin release by administration of 50 to 100 g glucose results in maximal splanchnic extraction (75%) of an ingested glucose load, whereas smaller amounts of glucose are retained to a lesser extent; (2) 100 g of glucose provide optimal conditions for performing an oral glucose tolerance test (OGTT), thereby provoking a relative as well as an absolute maximum of splanchnic glucose extraction; and (3) splanchnic uptake of pyruvate and lactate following ingestion of small amounts of glucose revert to a net output with utilization of increasing glucose loads.

Insulin production rate following glucose ingestion estimated by splanchnic C-peptide output in normal man.

Insulin production rate has been estimated in healthy male volunteers (n = 16), and evaluated with respect to splanchnic glucose exchange. Insulin production rate was calculated from splanchnic immunoreactive C-peptide output. C-peptide secretion was estimated by the hepatic venous catheter technique both in the basal state and for 2 h following ingestion of various glucose loads (0, 12.5, 25, 50, 75, and 100 g). The results demonstrate a basal insulin production rate of 0.017 +/- 0.002 U/min (mean +/- SEM) or 2.04 U/2 h. Values rose in a dose dependent manner from 2.6 +/- 1.1 U/2 h after ingestion of 12.5 g of glucose to 10.8 +/- 1.1 U/2 h following a glucose load of 100 g. Insulin retention by the liver was estimated at 0.012 +/- 0.001 U/min in the basal state, and ranged from 47-85% (70 +/- 2%) of production following an oral glucose load. It was also demonstrated 1) that the relative splanchnic glucose output was inversely related to the amount of ingested glucose, and reached a minimum when glucose in excess of 50 g was ingested; and 2) that hepatic glucose retention was directly proportional to insulin production rate (r = 0.83; p less than 0.001; n = 15). It is suggested that the adaptive capacity of the splanchnic bed to retain glucose depending on the amount of ingested glucose guarantees that splanchnic glucose output fluctuates in healthy man only within a narrow range.

Influence of Arginine on Splanchnic Glucose Metabolism in Man

To examine the mechanism of the arginine-induced rise in blood glucose concentration, splanchnic glucose output (SGO) and precursor uptake were studied during i.v. infusion of arginine (30 g/30 min) with and without somatostatin infusion (500 microgram/h, 90 min) in postabsorptive and in 60-h fasted healthy subjects. The hepatic venous catheter technique was employed. In the postabsorptive state, arginine infusion was accompanied by an eightfold and a fivefold increment, respectively, in the hepatic venous concentration of insulin and glucagon; SGO doubled and blood glucose increased by 30%. After cessation of arginine infusion, SGO and blood glucose returned to basal levels within 30 min. When both arginine and somatostatin were administered, glucagon rose threefold, whereas the insulin response was abolished. And while the rise in SGO during arginine infusion and its subsequent decline were uninfluenced by the simultaneous infusion of somatostatin, the rise in blood glucose was more pronounced and the glucose concentration remained elevated longer than in control studies without somatostatin. Splanchnic uptake of glucogenic precursors was uninfluenced by arginine infusion, with or without simultaneous somatostatin administration. In the 60-h fasted group, arginine infusion was accompanied by a minimal increase in insulin but a fivefold elevation of the glucagon level. Combined arginine and somatostatin infusion did not boost insulin significantly but the glucagon level rose threefold above the basal value. Basal SGO was 55% lower than in the postabsorptive state, and it rose in response to arginine administration (+50%) as well as during combined arginine and somatostatin infusion (+80%). No significant change in splanchnic uptake of glucogenic precursors was observed during arginine infusion with or without somatostatin administration. We conclude that (1) arginine infusion is accompanied by a rise in SGO and blood glucose due to arginine-induced stimulation of glucagon secretion, (2) the rise in SGO is caused primarily by glucagon-stimulated hepatic glycogenolysis, and (3) combined somatostatin and arginine administration is accompanied by a more marked rise in blood glucose due to hypoinsulinemia and reduced peripheral glucose utilization.